Background: Adiponectin, the most abundant adipokine derived from adipose tissue, exhibits a potent suppressive effect on the growth of breast cancer cells; however, the underlying molecular mechanisms for this effect are not completely understood. Fatty acid metabolic reprogramming has recently been recognized as a crucial driver of cancer progression. Adiponectin demonstrates a wide range of metabolic activities for the modulation of lipid metabolism under physiological conditions. However, the biological actions of adiponectin in cancer-specific lipid metabolism and its role in the regulation of cancer cell growth remain elusive. Methods: The effects of adiponectin on fatty acid metabolism were evaluated by measuring the cellular neutral lipid pool, free fatty acid level, and fatty acid oxidation (FAO). Colocalization between fluorescent-labeled lipid droplets and LC3/lysosomes was employed to detect lipophagy activation. Cell viability and apoptosis were examined by MTS assay, caspase-3/7 activity measurement, TUNEL assay, and Annexin V binding assay. Gene expression was determined by real time-quantitative polymerase chain reaction (RT-qPCR) and western blot analysis. The transcriptional activity of SREBP-1 was examined by a specific dsDNA binding assay. The modulatory roles of SIRT-1 and adiponectin-activated mediators were confirmed by gene silencing and/or using their pharmacological inhibitors. Observations from in vitro assays were further validated in an MDA-MB-231 orthotopic breast tumor model. Results: Globular adiponectin (gAcrp) prominently decreased the cellular lipid pool in different breast cancer cells. The cellular lipid deficiency promoted apoptosis by causing disruption of lipid rafts and blocking raft-associated signal transduction. Mechanistically, dysregulated cellular lipid homeostasis by adiponectin was induced by two concerted actions: 1) suppression of fatty acid synthesis (FAS) through downregulation of SREBP-1 and FAS-related enzymes, and 2) stimulation of lipophagy-mediated lipolysis and FAO. Notably, SIRT-1 induction critically contributed to the adiponectin-induced metabolic alterations. Finally, fatty acid metabolic remodeling by adiponectin and the key role of SIRT-1 were confirmed in nude mice bearing breast tumor xenografts. Conclusion: This study elucidates the multifaceted role of adiponectin in tumor fatty acid metabolic reprogramming and provides evidence for the connection between its metabolic actions and suppression of breast cancer.

Mesenchymal stromal cells (MSCs) have received attention as promising therapeutic agents for the treatment of various diseases. However, poor post-transplantation viability has been a major hurdle in MSC-based therapy, despite encouraging results in many inflammatory disorders and tissue repair. Recently, three dimensional (3D)-cultured MSCs (MSC_3D) were shown to have higher cell survival and enhanced anti-inflammatory effects, although the underlying mechanisms have not yet been elucidated. In this study, we investigated the molecular mechanisms by which MSC_3D gain the potential for enhanced cell viability. Herein, we found that macroautophagy/autophagy was highly induced and ROS production was suppressed in MSC_3D as compared to 2D-cultured MSCs (MSC_2D). Interestingly, inhibition of autophagy induction caused decreased cell viability and increased apoptotic activity in MSC_3D. Furthermore, modulation of ROS production was closely related to the survival and apoptosis of MSC_3D. We also observed that HMOX1 (heme oxygenase 1) was significantly up-regulated in MSC_3D. In addition, gene silencing of HMOX1 caused upregulation of ROS production and suppression of the genes related to autophagy. Moreover, inhibition of HIF1A (hypoxia inducible factor 1 subunit alpha) caused suppression of HMOX1 expression in MSC_3D, indicating that the HIF1A-HMOX1 axis plays a crucial role in the modulation of ROS production and autophagy induction in MSC_3D. Finally, the critical role of autophagy induction on improved therapeutic effects of MSC_3D was further verified in dextran sulfate sodium (DSS)-induced murine colitis. Taken together, these results indicated that autophagy activation and modulation of ROS production mediated via the HIF1A-HMOX1 axis play pivotal roles in enhancing the viability of MSC_3D.

Adiposity is associated with an increased risk of various types of carcinoma. One of the plausible mechanisms underlying the tumor-promoting role of obesity is an aberrant secretion of adipokines, a group of hormones secreted from adipose tissue, which have exhibited both oncogenic and tumor-suppressing properties in an adipokine type- and context-dependent manner. Increasing evidence has indicated that these adipose tissue-derived hormones differentially modulate cancer cell-specific metabolism. Some adipokines, such as leptin, resistin, and visfatin, which are overproduced in obesity and widely implicated in different stages of cancer, promote cellular glucose and lipid metabolism. Conversely, adiponectin, an adipokine possessing potent anti-tumor activities, is linked to a more favorable metabolic phenotype. Adipokines may also play a pivotal role under the reciprocal regulation of metabolic rewiring of cancer cells in tumor microenvironment. Given the fact that metabolic reprogramming is one of the major hallmarks of cancer, understanding the modulatory effects of adipokines on alterations in cancer cell metabolism would provide insight into the crosstalk between obesity, adipokines, and tumorigenesis. In this review, we summarize recent insights into putative roles of adipokines as mediators of cellular metabolic rewiring in obesity-associated tumors, which plays a crucial role in determining the fate of tumor cells.

Mesenchymal stem cell (MSC) therapy is an emerging treatment strategy to counteract metabolic syndromes, including obesity and its comorbid disorders. However, its effectiveness is challenged by various factors in the obese environment that negatively impact MSC survival and function. The identification of these detrimental factors will provide opportunities to optimize MSC therapy for the treatment of obesity and its comorbidities. Dysregulated production of adipokines, a group of cytokines and hormones derived from adipose tissue, has been postulated to play a pivotal role in the development of obesity-associated complications. Intriguingly, adipokines have also been implicated in the modulation of viability, self-renewal, proliferation, and other properties of MSC. However, the involvement of adipokine imbalance in impaired MSC functionality has not been completely understood. On the other hand, treatment of obese individuals with MSC can restore the serum adipokine profile, suggesting the bidirectionality of the adipokine–MSC relationship. In this review, we aim to discuss the current knowledge on the central role of adipokines in the crosstalk between obesity and MSC dysfunction. We also summarize recent advances in the use of MSC for the treatment of obesity-associated diseases to support the hypothesis that adipokines modulate the benefits of MSC therapy in obese patients.